Calorie Restriction Improves Beta Cell Function and Slows Beta Cell Aging
The practice of calorie restriction alters near all aspects of cellular biochemistry throughout the body. The result is improved function and modestly slowed aging, an evolved response to low nutrient levels that serves to increase the odds of surviving a famine to reproduce once plenty returns. Seasonal famine is the most common such circumstance, and while the calorie restriction response appears to be near universal across all forms of life, short-lived species exhibit a much greater extension of life span as a result than is the case for long-lived species. A season is a sizable fraction of a mouse life span, but not of a human life span. So mice can live up to 40% longer on a low calorie diet, while humans likely gain only a few years.
Since calorie restriction changes just about everything for the better in the aging body, one can find any number of papers examining one very specific aspect of the calorie restriction response. Today's open access paper, for example, is focused on how beta cells are improved, and their functional decline with aging is slowed, in calorie restricted mice. Beta cells reside in the pancreas, produce insulin, and are thus of central importance in insulin metabolism and glucose metabolism. This portion of overall metabolism affects the pace of aging, as illustrated by the accelerated aging exhibited by diabetic patients.
Beta cells secrete insulin in response to increases in blood glucose levels to sustain normal glucose homeostasis for an entire lifetime. Several studies have investigated the impact of aging on beta cells and established that aging beta cells have compromised expression of transcription factors (TFs) and re-organization of gene regulatory networks (GRNs) that maintain beta cell identity, accumulation of islet fibrosis, inflammation, and ER stress, reduced KATP channel conductance, loss of coordinated beta cell calcium dynamics, impaired beta cell autophagy and accumulation of beta cell DNA damage, and/or beta cell senescence. When combined with an unhealthy lifestyle during old age, these aging signatures could pre-dispose beta cells to failure and lead to type 2 diabetes (T2D) onset.
Caloric restriction (CR) and CR-mimicking approaches (e.g., time-restricted feeding (TRF)) can prolong organismal longevity and delay aging from yeast to non-human primates. These beneficial effects are associated with improved glucose homeostasis due to prolonged fasting and enhanced peripheral insulin sensitivity, enhanced insulin signaling, lower adiposity, enhanced mitochondrial homeostasis and lower ATP generation, increased autophagy, enhanced protein homeostasis and reduced ER stress and inflammation. In the pancreas, 20-40% CR or CR achieved via TRF are linked to lower islet cell mass in lean mice, whereas in pre-diabetic mice, CR restores normal beta cell secretory function, identity, and preserves beta cell mass in a process dependent on activation of beta cell autophagy via Beclin-2. In patients with a recent T2D diagnosis, the efficacy of extreme CR (average of 835 kcal/day or greater than 50% CR based on a 2000 kcal/day diet) to reverse T2D depends on the capacity of beta cells to recover from previous exposure to a T2D metabolic state. However, how beta cells adapt during CR, and whether CR can delay the hallmarks of beta cell aging remains largely unknown.
We investigated these questions by exposing adult male mice to mild CR (i.e., 20% restriction) for up to 12 months and applied comprehensive in vivo and in vitro metabolic phenotyping of beta cell function followed by single-cell multiomics and multi-modal high-resolution microscopy pipelines. Our data reveals that CR reduces the demand for beta cell insulin release necessary to sustain euglycemia by increasing peripheral insulin sensitivity. Ad-libitum (AL) consumption of a diet with reduced caloric intake failed to trigger a similar phenotype, thus indicating that CR and CR-associated fasting periods are required for this adaptive metabolic response. During CR, the transcriptional architecture of beta cells is re-organized to promote a largely post-mitotic and long-lived phenotype with enhanced cell homeostasis and mitochondrial structure-function. This is associated with reduced onset and/or expression of beta cell aging and senescence signatures. When exposed to a high-fat diet (HFD), CR beta cells upregulate insulin release, however they have a compromised adaptive response due to limited cell proliferation resulting in reduced beta cell mass. Therefore, our results provide a molecular footprint of how CR modulates adult beta cell function and insulin sensitivity to promote beta cell longevity and delay aging in mice.